To the present time, in the production of a radioactive ligand having a 18F-labeled fluorobenzene ring, an electrophilic substitution reaction or a nucleophilic substitution reaction has been used.
In the electrophilic substitution reaction, a phenyltin derivative has been used as a labeling material. And 18F fluorine gas has been used as a fluorine reagent. The electrophilic substitution reaction, however, has a disadvantage in that the labeling efficiency and the reaction yield are low. Furthermore, the specific activity, which is an important factor in radiopharmaceuticals, of the compound obtained by this substitution reaction is only a few mCi/μmol.
To overcome this disadvantage, a nucleophilic substitution reaction of a benzene ring by 18F has often been used. In the nucleophilic substitution reaction, as compared with an electrophilic substitution reaction, the reaction yield is high and the obtained compound is expected to have a high level of specific activity.
However, the most noticeable characteristic of the nucleophilic substitution reaction is that the presence or absence of substituents on a benzene ring or the position and kind of the substituents has an effect not only on the yield of the reaction, but also on the progress of the reaction. Specifically, the nucleophilic substitution reaction requires an electron-withdrawing substituent (e.g., NO2, CN, CHO, COOMe, or COOH) at the para- or ortho-position of the benzene ring. It also requires NO2, Cl, Br, I, +NMe3 or the like as a leaving group. Thus, the production, utilizing the nucleophilic substitution, of a radioactive ligand having a fluorobenzene ring places severe requirements on the substrate, and therefore, lacks general usability.
In such circumstances, the present inventors thought of an idea that the reaction of a diphenyliodonium salt with [18F]F− could be used to synthesize a radioactive ligand having a 18F-labeled fluorobenzene ring.
There have been reported various methods for synthesizing a diphenyliodonium salt as a labeled precursor. However, in any one of the methods, the synthesis must be carried out under severe conditions, for example, using an oxidant. Thus, it is difficult to synthesize a diphenyliodonium salt, which is expected to be used for various radioactive ligands having complex structures, by any one of the conventional methods. To the present time, in fact, there had been reported no radioactive ligand which was synthesized utilizing the reaction of a diphenyliodonium salt with [18F]F− except for the synthesis of only simple (substituents: H, Me, Cl, OMe, etc.) [18F]fluorobenzene derivatives.
A method for producing hydroxy(tosyloxy)iodobenzene is described in Non-Patent Document 1. A method for producing diaryliodonium triflates is described in Non-Patent Document 2. And the reaction of diaryliodonium triflate with [18F]F− is described in Non-Patent Document 3.
Non-Patent Document 1: G. F. Koser et al., J. Org. Chem., 42, 1476 (1977)
Non-Patent Document 2: T. Kitamura et al., Synthesis, 147 (1994)
Non-Patent Document 3: V. W. Pike et al., J. Chem. Soc. Chem. Commun., 2215 (1995)